Abstract
Background
The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.
Methods
This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.
Results
Brd1+/- mice displayed cerebral histone H3K14 hypo-acetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNAseq analyses of cortical and striatal micropunches from Brd1+/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk including several schizophrenia GWAS risk genes (e.g. calcium channel subunits (Cacna1c and Cacnb2), cholinergic muscarinic receptor 4 (Chrm4), dopamine receptor D2 (Drd2), and transcription factor 4 (Tcf4)). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g. glutamatergic, monaminergic, calcium, cAMP, DARPP-32, and CREB signaling).
Conclusions
Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.
The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.
Methods
This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.
Results
Brd1+/- mice displayed cerebral histone H3K14 hypo-acetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNAseq analyses of cortical and striatal micropunches from Brd1+/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk including several schizophrenia GWAS risk genes (e.g. calcium channel subunits (Cacna1c and Cacnb2), cholinergic muscarinic receptor 4 (Chrm4), dopamine receptor D2 (Drd2), and transcription factor 4 (Tcf4)). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g. glutamatergic, monaminergic, calcium, cAMP, DARPP-32, and CREB signaling).
Conclusions
Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.
| Original language | English |
|---|---|
| Journal | Biological psychiatry |
| Early online date | 15 Sept 2016 |
| DOIs | |
| Publication status | E-pub ahead of print - 15 Sept 2016 |
Keywords
- BRD1
- knockout mouse
- schizophrenia
- behavior
- electrophysiology
- RNAseq
- monoaminergic neurotransmission
- cyclic AMP response element-binding protein (CREB)
- DARPP32 signaling